Mechanistic insights into SOCS5-related DNA damage and cellular senescence in diabetic retinopathy

Apr 1, 2026Cell death discovery

How SOCS5 May Link DNA Damage and Cell Aging in Diabetic Eye Disease

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

SOCS5 was significantly upregulated in diabetic retinopathy.

SOCS5 knockdown reduced retinal tissue damage, vascular leakage, and cell death in diabetic retinopathy mice.
Decreased DNA damage and cellular aging were observed in high glucose-stimulated human retinal cells with reduced SOCS5.
SOCS5 influences diabetic retinopathy progression by regulating Cyclin-Dependent Kinase Inhibitor 1 A (CDKN1A), which is involved in cell cycle arrest.
POU2F1 was identified as an upstream activator of SOCS5, indicating a novel signaling pathway in diabetic retinopathy.
Inhibiting both POU2F1 and SOCS5 improved diabetic retinopathy-related issues in mice.

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This study elucidated the mechanistic role of the Suppressor of Cytokine Signaling 5 (SOCS5) in diabetic retinopathy (DR), focusing on DNA damage and cellular senescence pathways. Utilizing both in vitro (high glucose (HG)-induced human retinal microvascular endothelial cells (HRMECs)) and in vivo (streptozotocin-induced DR mouse models) approaches, we demonstrated that SOCS5 was significantly upregulated in DR. SOCS5 knockdown mitigated retinal tissue damage, vascular leakage, and apoptosis in DR mice while reducing DNA damage and cellular senescence in HG-stimulated HRMECs. Mechanistically, SOCS5 promoted DR progression by regulating the expression of Cyclin-Dependent Kinase Inhibitor 1 A (CDKN1A), a key mediator of cell cycle arrest and senescence. Furthermore, we identified POU Class 2 Homeobox 1 (POU2F1) as an upstream transcriptional activator of SOCS5, forming a novel POU2F1-SOCS5-CDKN1A axis that drove DR pathogenesis. Inhibition of POU2F1 and SOCS5 ameliorated DR-related pathology in mice, suggesting a novel therapeutic strategy. These findings reveal a previously unrecognized signaling pathway in DR and highlight SOCS5 as a promising target for intervention.

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Mechanistic insights into SOCS5-related DNA damage and cellular senescence in diabetic retinopathy

Abstract

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